Parkinson's disease, dementia with Lewy bodies and multiple system atrophy are characterised by abnormal neuroglial α-synuclein accumulation. These α-synucleinopathies have in common parkinsonism and non-motor features including orthostatic hypotension (OH) and cognitive impairment. However, the nature of the relationship between OH and cognitive impairment is unclear. We therefore systematically reviewed the literature for evidence of an association between OH and cognitive impairment in α-synucleinopathies and discuss possible mechanisms and implications of this relationship. Abstracts from 313 original research articles were surveyed, and a total of 132 articles were considered for this review. Articles were stratified as: ‘direct-evidence studies’ based on the direct assessment for a relationship between OH and cognitive impairment in α-synucleinopathies, and ‘indirect-evidence studies’ based on an association being referred to as a secondary outcome. Ten ‘direct-evidence papers’ were identified, seven of which reported a positive association between OH and cognitive impairment, while seven of 12 ‘indirect-evidence papers’ similarly did as well. The papers that reported no association between OH and cognitive impairment used less sensitive measures of cognition. A relationship between OH and cognitive impairment in patients with α-synucleinopathies exists, but the underlying mechanisms remain unclear. Three hypotheses are proposed: (1) OH and cognitive impairment occur concurrently due to diffuse brain and peripheral deposition of α-synuclein, (2) OH-mediated cerebral hypoperfusion impairs cognition and (3) the two act synergistically to accelerate cognitive decline. Longitudinal neuroimaging studies and clinical trials may help clarify the nature of this relationship.
- PARKINSON'S DISEASE
- LEWY BODY
- MULTISYSTEM ATROPHY
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Contributors SJU and MM involved in preparation of project conception. SJU involved in review execution. Graphic design was made by SJU and ADR. SJU prepared manuscript draft. Manuscript review and critique were performed by ADR, BJM, AJE, JBR, AEL and MM.
Funding This project was supported by a Clinical Fellowship award from Parkinson's Society Canada.
Competing interests SJU and ADR have nothing to disclose. BJM has received peer-reviewed research support from the Canadian Institutes of Health Research. AJE is supported by the NIH (1K23MH092735); has received grant support from Great Lakes Neurotechnologies and the Michael J Fox Foundation; personal compensation as a consultant/scientific advisory board member for Abbvie, TEVA, Impax, Merz, Acadia, Cynapsus, Lundbeck and USWorldMeds; royalties from Lippincott Williams & Wilkins and Cambridge University Press; and honoraria from Abbvie, USWorldMeds, Lundbeck, Acadia, the American Academy of Neurology and the Movement Disorders Society. JBR receives salary support from the Wellcome Trust (103838) and has received peer-reviewed research support from Wellcome Trust, Medical Research Council, National Institute for Health Research, PSP-Association, Parkinson's UK, Alzheimer's Research UK, The Evelyn Trust James F McDonnell Foundation and an academic research grant from AZ-Medimmune. AEL has served as an advisor for Abbvie, Allon Therapeutics, Avanir Pharmaceuticals, Biogen Idec, Boerhinger-Ingelheim, Bristol Myers Squibb, Ceregene, Cipla, Intekrin, Lilly, Medtronic, Merck, Novartis, NeuroPhage Pharmaceuticals, Teva and UCB; received honoraria from Medtronic, Teva, UCB and AbbVie; received grants from Brain Canada, Canadian Institutes of Health Research, Edmond J Safra Philanthropic Foundation, Michael J. Fox Foundation, Ontario Brain Institute, National Parkinson Foundation, Parkinson Society Canada, Physicians Services Incorporated (PSI), Tourette Syndrome Association and W. Garfield Weston Foundation; received publishing royalties from Saunders, Wiley-Blackwell, Johns Hopkins Press and Cambridge University Press; and has served as an expert witness in cases related to the welding industry. MM has served as an advisor to Bioscape Medical Imaging CRO, Novartis and UCB; received honoraria from Novartis; received royalties from Henry Stewart Talks; received an investigator-initiated research grant from Teva; received contract research support from Roche and Novartis; received peer-reviewed research support from Canadian Institutes of Health Research, Ministry of Economic Development and Innovation (Ontario), Weston Brain Institute, Sunnybrook AFP Innovation Fund, Washington University, Parkinson Society Canada, Alzheimer's Drug Discovery Foundation, Brain Canada and Ontario Brain Institute; and received salary support from the Department of Medicine at Sunnybrook Health Sciences Centre and University of Toronto and from the Sunnybrook Foundation.
Patient consent Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.
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